title: Functionally deregulated AML1/RUNX1 cooperates with BCR-ABL to induce a blastic phase-like phenotype of chronic myelogenous leukemia in mice.
abstract: Patients in the chronic phase (CP) of chronic myelogenous leukemia (CML) have been treated successfully following the advent of ABL kinase inhibitors, but once they progress to the blast crisis (BC) phase the prognosis becomes dismal. Although mechanisms underlying the progression are largely unknown, recent studies revealed the presence of alterations of key molecules for hematopoiesis, such as AML1/RUNX1. Our analysis of 13 BC cases revealed that three cases had AML1 mutations and the transcript levels of wild-type (wt.) AML1 were elevated in BC compared with CP. Functional analysis of representative AML1 mutants using mouse hematopoietic cells revealed the possible contribution of some, but not all, mutants for the BC-phenotype. Specifically, K83Q and R139G, but neither R80C nor D171N mutants, conferred upon BCR-ABL-expressing cells a growth advantage over BCR-ABL-alone control cells in cytokine-free culture, and the cells thus grown killed mice upon intravenous transfer. Unexpectedly, wt.AML1 behaved similarly to K83Q and R139G mutants. In a bone marrow transplantation assay, K83Q and wt.AML1s induced the emergence of blast-like cells. The overall findings suggest the roles of altered functions of AML1 imposed by some, but not all, mutants, and the elevated expression of wt.AML1 for the disease progression of CML.
authors.affiliation: Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan ; Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Shinobu
authors.initials: S
authors.lastname: Tsuzuki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Minami
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Abe
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Masao
authors.initials: M
authors.lastname: Seto
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000818:Animals; D001752:Blast Crisis / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D034741:RNA, Small Interfering; C493726:Runx1 protein, mouse; D016044:Fusion Proteins, bcr-abl